Prevention of cardiac hypertrophy with omega 3-fatty acids: Potential cellsignaling targets

Epidemiological studies of Greenland Eskimos and Japanese have suggested th at eating fish oil and marine animals can prevent heart disease. The benefi cial effects of fish oils are attributed to their omega 3-fatty acid (O3FA) content, particularly, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexa enoic acid (DHA, 22:6n-3). DHA and EPA in the diet influence the fatty acid composition of plasma membrane phospholipids in cardiac tissues, which may affect cardiac cell functions. However, very little is known about the cel lular and molecular mechanisms that mediate O3FA-induced cardio-protective effects. This review describes the potential cellular targets that can be m odulated by O3FAs to regulate cardiac-related illnesses, particularly, card iomyocyte hypertrophy. Among various biochemical derangements, the increase in intracellular Ca2+ ([Ca2+](i)) allows the development of cardiac hypert rophy. Elevation of [Ca2+](i) acts as a central intracellular signaling sys tem by which hormones and growth factors regulate many different processes, such as secretion, metabolism, cell growth, differentiation, and eel contr actility. Recent studies clearly suggest that O3FAs have profound effects o n reducing [Ca2+](i) levers by regulating both influx of Ca2+ through Ca2channels and mobilization of Ca2+ from intracellular stores. These fatty ac ids modulate Ca2+ current through the L-type calcium channels, and the effe cts occur within minutes of adding EPA or DHA to the medium. O3FAs can also regulate calcium mobilization from intracellular stores by affecting phosp hatidylinositol cycle, phospholipase C activities, and inositol 1, 4, 5 tri sphosphate generation. The effect of O3FAs on reducing the [Ca2+](i) levels could be one of the mechanisms for preventing cardiac hypertrophy. In addi tion to affecting [Ca2+](i) levels, these fatty acids can also affect other signaling pathways, including alterations in receptor affinity and density , activities of adenylate and guanylate cyclase, and cyclic nucleotide phos phodiesterase activities. There is no direct evidence that O3FAs affect src , ras, and MAP kinase signal transduction pathways in cardiac tissues, but in other cellular systems these pathways can be modulated by O3FAs. It ther efore appears that a blockade of src, ras, and MAP kinase pathways, which i s known to be involved in the development of cardiac hypertrophy, could be an effective target for O3FAs. Another important process in the development of cardiac hypertrophy is the activation of protein kinase C (PKC) isoenzy mes. PKC activation leads to stimulation of specific pathways that mediate protein synthesis in cardiomyocytes. There is clear evidence that O3FAs aff ect the translocation and activation of PKC in cardiac tissues through mult iple mechanisms. The modulation of PKC activities therefore could be a pote nt target in regulating cardiac hypertrophy and other cardiac-related abnor malities. In conclusion, these recent studies suggest that O3FAs could prev ent the development of hormonal-induced cardiac hypertrophy by acting on mu ltiple cellular signaling pathways.